Major Depressive Disorder (MDD) is a common, disabling psychiatric illness characterized by persistent low mood, anhedonia, cognitive disturbances, and somatic symptoms. It affects over 264 million people globally and is recognized as a leading cause of disability and disease burden across all age groups [1]. Traditionally understood in terms of neurochemical imbalances and psychosocial stressors, MDD is now increasingly associated with underlying biological mechanisms such as inflammation, neuroendocrine dysregulation, and oxidative stress [2].

Oxidative stress refers to an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defense mechanisms. This imbalance leads to cellular injury, particularly in lipid membranes, proteins, and DNA. Emerging evidence indicates that oxidative stress contributes to the pathophysiology of several neuropsychiatric conditions, including depression, by inducing neuroinflammation, neuronal apoptosis, and hippocampal atrophy [3]. Key biomarkers like malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC) have been extensively studied in this context and show significant alterations in patients with MDD [4].

Globally, meta-analyses and case-control studies suggest that individuals with MDD consistently exhibit higher levels of oxidative markers and lower levels of antioxidants when compared to healthy controls [5]. For instance, a European cohort study reported significantly elevated serum MDA and reduced superoxide dismutase (SOD) activity in depressed patients, pointing toward ongoing lipid peroxidation and compromised cellular defense [6]. Similarly, studies from Asia and North America have highlighted the diagnostic and prognostic relevance of oxidative markers in identifying disease severity and therapeutic response.

In India, where mental health disorders often go underreported or undertreated due to stigma and lack of awareness, there is growing recognition of the biological basis of depression. Indian studies have documented increased oxidative stress and reduced antioxidant enzyme activity in MDD patients, though findings vary due to methodological differences and limited sample sizes [7]. In West Bengal, particularly in tertiary teaching institutions, recent interest has grown in integrating biochemical markers into routine psychiatric evaluation. However, few studies have comprehensively analyzed oxidative stress markers in MDD from a pathology-laboratory standpoint, resulting in a significant knowledge gap in this region [8].

This study was therefore undertaken to evaluate oxidative stress markers in patients diagnosed with Major Depressive Disorder using a pathology-based approach. It aims to identify key biochemical changes that may correlate with the clinical profile of MDD, provide insights into the biological underpinnings of the disorder, and support future integration of laboratory markers into routine psychiatric assessment and treatment planning.

This was a hospital-based, observational, cross-sectional study conducted over a period of one year in the Department of Psychiatry in collaboration with the Department of Pathology at ESI-PGIMSR, ESIC Medical College & Hospital, Joka, Kolkata. The study aimed to evaluate oxidative stress marker alterations among patients diagnosed with Major Depressive Disorder (MDD) as per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria.

A total of 60 patients aged between 18 and 60 years, newly diagnosed or previously diagnosed cases of MDD currently in an active episode and not on antioxidant supplements or anti-inflammatory medications, were included. Participants with comorbid psychiatric disorders, chronic medical illnesses (e.g., diabetes, hypertension, renal or hepatic disease), substance abuse, or pregnancy were excluded to eliminate confounding variables.

Patients were selected using a purposive sampling method from outpatient and inpatient psychiatric services. After obtaining informed written consent, each participant underwent a structured clinical interview to confirm the diagnosis and assess the severity of depression using standardized rating scales. Demographic and clinical data were recorded, and detailed history was taken to rule out exclusion criteria.

Venous blood samples were collected under aseptic precautions after an overnight fast and were immediately processed in the pathology laboratory. Biochemical analysis included serum levels of oxidative stress markers such as malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), which were measured using validated spectrophotometric methods. MDA was assessed using thiobarbituric acid-reactive substances (TBARS), NO by the Griess reaction, and TAC using the FRAP (ferric reducing antioxidant power) assay.

Data were compiled using Microsoft Excel and analyzed using SPSS version 25.0. Descriptive statistics including means, standard deviation, and frequencies were calculated. Differences in oxidative stress marker levels were compared between subgroups based on depression severity using Student’s t-test and one-way ANOVA, wherever appropriate. A p-value less than 0.05 was considered statistically significant.

Ethical clearance was obtained from the Institutional Ethics Committee before commencing the study, and all ethical guidelines were adhered to throughout the research process.

A total of 60 patients with Major Depressive Disorder were included in the study. The majority belonged to the 31–45 year age group (46.7%), with a female predominance (56.7%). Most participants (55%) had moderate depression, while 26.7% had severe depression, and 18.3% had mild depression. Regarding illness duration, 43.3% had been symptomatic for 6–12 months.

Biochemical analysis revealed significantly elevated levels of oxidative stress markers in the study population. The mean malondialdehyde (MDA) level was 3.92 ± 0.84 nmol/mL, with 75% of patients showing elevated values. Nitric oxide (NO) levels were also increased, with a mean of 52.4 ± 9.1 µmol/L and 65% of patients above the reference range. Conversely, the mean total antioxidant capacity (TAC) was markedly reduced (0.92 ± 0.26 mmol/L), with 80% of patients showing subnormal levels.

When stratified by depression severity, patients with severe depression had the highest mean MDA (4.45 nmol/mL) and NO (57.3 µmol/L) levels, along with the lowest TAC (0.72 mmol/L). Statistical analysis using ANOVA revealed a significant association between increasing severity of depression and oxidative imbalance (p < 0.05), indicating that oxidative stress markers worsen in parallel with clinical severity.

Table 1: Demographic and Clinical Profile of Patients (n = 60)

Table 2: Oxidative Stress Marker Levels Among MDD Patients (n = 60)

Table 3: Comparison of Oxidative Stress Markers by Depression Severity (n = 60)

This study demonstrated a significant elevation of oxidative stress markers—malondialdehyde (MDA) and nitric oxide (NO)—along with a reduction in total antioxidant capacity (TAC) among patients with Major Depressive Disorder (MDD). Furthermore, the levels of oxidative stress biomarkers were found to correlate positively with the severity of depression, highlighting their potential role in the pathophysiology and progression of MDD.

The elevated MDA levels observed in this study (mean 3.92 nmol/mL) are consistent with the findings of Bilici et al., who reported significantly higher MDA levels in MDD patients compared to healthy controls, indicating increased lipid peroxidation and neuronal membrane damage [9]. Similarly, Kunz et al. also noted increased MDA and NO levels in depressed individuals, suggesting that oxidative injury is not just a byproduct of stress but may contribute to the neurodegenerative aspects of depression [10].

In line with these findings, our study found elevated NO levels in 65% of patients, with a mean of 52.4 µmol/L, which aligns with the study by Gałecki et al., where increased nitrosative stress was linked to depressive symptomatology and reduced neuronal plasticity [11]. This excess NO may interact with superoxide to form peroxynitrite, a potent free radical that causes further neuronal damage.

The marked reduction in TAC in this study (mean 0.92 mmol/L) underscores the impaired antioxidant defense in MDD patients. Maes et al. emphasized the critical role of diminished antioxidant reserves—particularly in enzymes like SOD, catalase, and glutathione peroxidase—in facilitating neuroinflammation and hippocampal atrophy in depression [12]. Ng et al. further highlighted that antioxidant supplementation could be a beneficial adjunct to antidepressants, especially in treatment-resistant cases [13].

Our observation that oxidative imbalance worsens with increasing depression severity is in agreement with the work of Sarandol et al., who showed a significant correlation between oxidative stress markers and Hamilton Depression Rating Scale scores, suggesting that biochemical markers could serve as objective indicators of disease severity [14]. Additionally, Black et al. found that oxidative changes persisted even in patients under treatment, reinforcing the chronicity of oxidative stress in MDD and the need for early intervention [15].

Together, these findings support the growing consensus that oxidative stress is not merely an epiphenomenon but an active contributor to the pathophysiology of depression. The pathology-based biochemical assessment used in this study reinforces the value of integrating oxidative stress profiling into routine psychiatric evaluation to guide both prognostication and personalized treatment strategies.

This study demonstrated a significant association between Major Depressive Disorder and elevated oxidative stress, as evidenced by increased serum levels of malondialdehyde (MDA) and nitric oxide (NO), and decreased total antioxidant capacity (TAC). The severity of depression showed a proportional relationship with the degree of oxidative imbalance, suggesting that oxidative stress may not only be a marker but also a mechanistic contributor to the pathophysiology of MDD. These findings highlight the potential clinical utility of oxidative stress markers in the assessment, monitoring, and individualized management of depression.

Limitations and Recommendations

The study was limited by its cross-sectional design, which restricts causal inferences, and the absence of a healthy control group for direct comparison. Additionally, dietary habits, lifestyle factors, and medication history, which could influence oxidative status, were not controlled. Future research should include longitudinal follow-up with larger, more diverse samples and control groups. It is recommended to incorporate oxidative stress profiling in psychiatric settings to support biomarker-based diagnosis and explore antioxidant therapies as adjuncts in depression management.

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